Deletion of Adenosine A2A Receptors From Astrocytes Disrupts Glutamate Homeostasis Leading to Psychomotor and Cognitive Impairment: Relevance to Schizophrenia

Abstract

BACKGROUND Adenosine A2A receptors (A2AR) modulate dopamine and glutamate signaling and thereby may influence some of the psychomotor and cognitive processes associated with schizophrenia. Because astroglial A2AR regulate the availability of glutamate, we hypothesized that they might play an unprecedented role in some of the processes leading to the development of schizophrenia, which we investigated using a mouse line with a selective deletion of A2AR in astrocytes (Gfa2-A2AR knockout [KO] mice]. METHODS We examined Gfa2-A2AR KO mice for behaviors thought to recapitulate some features of schizophrenia, namely enhanced MK-801 psychomotor response (positive symptoms) and decreased working memory (cognitive symptoms). In addition, we probed for neurochemical alterations in the glutamatergic circuitry, evaluating glutamate uptake and release and the levels of key proteins defining glutamatergic signaling (glutamate transporter-I [GLT-I], N-methyl-D-aspartate receptors [NMDA-R] and α-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors [AMPA-R]) to provide a mechanistic understanding of the phenotype encountered. RESULTS We show that Gfa2-A2AR KO mice exhibited enhanced MK-801 psychomotor response and decreased working memory; this was accompanied by a disruption of glutamate homeostasis characterized by aberrant GLT-I activity, increased presynaptic glutamate release, NMDA-R 2B subunit upregulation, and increased internalization of AMPA-R. Accordingly, selective GLT-I inhibition or blockade of GluR1/2 endocytosis prevented the psychomotor and cognitive phenotypes in Gfa2-A2AR KO mice, namely in the nucleus accumbens. CONCLUSIONS These results show that the dysfunction of astrocytic A2AR, by controlling GLT-I activity, triggers an astrocyte-to-neuron wave of communication resulting in disrupted glutamate homeostasis, thought to underlie several endophenotypes relevant to schizophrenia.

Adenosine A2A receptor and ecto-5′-nucleotidase/CD73 are upregulated in hippocampal astrocytes of human patients with mesial temporal lobe epilepsy (MTLE)

“…Activation of astrocytic A 2A receptor may result in increases in the extracellular levels of glutamate leading to neuronal excitation and/or excitotoxicity. The mechanism underlying the A 2A receptor-mediated control of glutamate outflow by astrocytes seems to involve activation of protein kinase A and intracellular Ca 2+ mobilization [11], while the mechanism responsible for the downmodulation of glutamate uptake by the A 2A receptor depends on a decrease in Na + /K + -ATPase activity, and, thereby, the disruption of the transmembrane Na + gradient [13] that is required for glutamate uptake by GLT-1 [55]. Although the intracellular transduction pathway implicated in the A 2A receptor-mediated inhibition of glutamate uptake in astrocytes may differ, the final result Fig.…”

Aberrant adenosine A2A receptor signaling contributes to neurodegeneration and cognitive impairments in a mouse model of synucleinopathy

“…Western blot analysis as we described previously (Augusto et al, 2013;Matos et al, 2015;Rebola et al, 2005a). Briefly, after determination of protein concentration, samples were diluted with five volumes of SDS-PAGE buffer.…”

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

“…A1 and A3 are Gi‐coupled, while A2A and A2B are Gs‐coupled receptors which inhibit and trigger, respectively, cyclic AMP (cAMP)‐mediated signaling. A2A receptors are highly expressed in the brain and have been implicated in diverse neuropathologies, including PD, ischemic brain injury, traumatic brain injury and schizophrenia (Chen et al, 2007; Matos et al, 2015). A2A receptors on glial cells and their impact on the neuroinflammatory and neuromodulatory processes are likely to be involved in these diseases.…”

“…In line with this speculation, there has been some evidence showing that caffeine, whose main target is A2A receptors, can improve normal memory function or even prevent AD symptoms in older adults (Arendash and Cao, 2010; Borota et al, 2014; Carman, Dacks, Lane, Shineman, & Fillit, 2014). However, the case is not clear, because deletion of astrocytic A2A receptors disrupts glutamate homeostasis, leading to psychomotor and cognitive impairments which resemble schizophrenia (Matos et al, 2015). …”